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The Effects of Zn2+ on the Binding of the BDNF Prodomain with Sorcs2

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The Effects of Zn2+ on the Binding of the BDNF Prodomain with Sorcs2 The Effects of Zn2+ on the Binding of the BDNF Prodomain with SorCS2 on Neuronal Function and Structure: Implications for Learning and Memory Caroline Pennacchio Briarcliff Manor High School The Effects of Zn2+ on the Binding of the BDNF Prodomain with SorCS2 on Neuronal Function and Structure:Implications for Learning and Memory Caroline Pennacchio Briarcliff High School, Briarcliff Manor, NY Neurotrophic factors are types of ligands found throughout the brain and are secreted by neurons to other neurons. They are in charge of regulating cell proliferation, differentiation, axon and dendrite growth, synaptogenesis, and synaptic function and plasticity. The four main ligands that interact in the brain are BDNF, NGF, NT-3 and NT-4/5. Although many times the functions of proneurotrophins in the brain are ignored, pro-neurotrophins have the ability to interact with p75 neurotrophin with high affinity, which demonstrates that the pro-region could be paramount to p75 signaling despite the ability of mature neurotrophins such as NGF to bind with p75. Furthermore, proBDNF acts in vivo as a biologically active factor regulating hippocampal structure, and synaptic transmission, and plasticity, which mature BDNF does not impact. Small changes in the human BDNF gene can lead to a Val66Met substitution within the prodomain. This single-nucleotide polymorphism (SNP) of BDNF has been linked with depression, memory alterations, and anxiety disorders and substitution induces structural changes in the protein.This study was conducted in order to determine the consequences of growth contraction and synapse elimination. Previously the impacts of the Val66Met polymorphism of BDNF on prodomain structure were determined to impact the structure and function of the protein produced altering growth cone retraction. Previously, a 28% binding differential of the Val and Met isoforms was seen. Therefore, the binding of the two isoforms of prodomain was examined with SorCS2 in the presence of Zn2+. However, the binding of the Met and Val isoforms appeared to be the same which should not have occurred as binding differences were seen previously. There are plans in place for the continuation of the research on this change to help reverse the depressional impacts of these SNPs. Review of Literature The brain is divided into the frontal, parietal, temporal and occipital lobes, each of which is responsible for different functions in the brain. In terms of memory, the frontal lobe works to coordinate transient working memory and working memory. The hippocampus, a small, pea- sized region in the center of the brain, works to maintain plasticity through the use of negative and positive remodeling which leads to memory formation. Furthermore, different molecules participate in neural connections leading to the production of Brain-derived neurotrophic factor (BDNF) which increases hippocampal neurogenesis, and alters neuronal function. Neurotrophic factors are types of ligands found throughout the brain and are secreted by neurons to other neurons. In charge of regulating cell proliferation, differentiation, axon and dendrite growth, synaptogenesis, and synaptic function and plasticity, (Reichardt, 2006, Lu, B, Pang, PT, Woo. N.H., 2005, Minichiello L, 2009) neurons function interdependently to send signals along an axon to the cell body and axon of the neighboring neurons. The four main neurotrophic ligands in the brain are BDNF, NGF, NT-3 and NT-4/5. Each of these ligands has the ability to bind to p75 along with a specific neurotrophin receptor known as a Trk receptor. NGF binds with TrkA, BDNF and NT-4/5 bind with Trk B, and NT-3 binds with TrkC (Bothwell, 1991). However, BDNF and NT-4/5 may be referred to as “functionally redundant,” because of their identical Trk compound binding patterns (Chao 2003). Secreted in an activity and calcium ion dependent manner, BDNF may be involved in controlling synaptic transmission and long-term synaptic plasticity because of its ability to promote neurogenesis. Additionally, the secretion of BDNF as a response to activity and calcium ion production represents an important mechanism underlying local and synapse-specific BDNF modulation (Lu, 2003). Changes occur in genes in the form of single nucleotide polymorphisms (SNP). A SNP of BDNF results in a Val66Met substitution in the pro domain region, and has been linked with depression, memory alterations, and anxiety disorders in humans because of the internal disordering of the prodomain and the Val66Met substitution which induce structural changes (Anastasia et al., 2013). While BDNF is responsible for many of the main functions of neurons, NT-4/5 also activates TrkB which in turn activates the tyrosine kinase compound activation of PI3K (phosphatidylinositol 3kinase) (Chao, 2003). There are two main types of neurotrophins: proneurotrophins and mature neurotrophins. While pro-neurotrophins consist of about 270 amino acids, with the pro-region consisting of approximately 120 amino acids (Seidah et al., 1996), mature neurotrophins are different from proneurotrophins in both structure and function. First synthesized as precursors, proneurotrophins are then proteolytically cleaved in trans-Golgi by furin or secretory granules by pro-protein contervases. This results in the formation of mature neurotrophins (the “pro” region has been removed) (Seidah el al., 1996) and the formation of the mature domain (proBDNF splits into BDNF and the prodomain). Pro and mature neurotrophins have opposite functional effects resulting from their diverse interactions with TrkA and p75 receptors. However, the extracellular cleavages that are created during the formation of the mature domain demonstrate how synaptic functions of neurotrophins can be controlled (Lu, 2003). Although many times the functions of proneurotrophins in the brain are ignored, pro-neurotrophins have the ability to interact with p75 neurotrophin with high affinity, which demonstrates that the pro-region could be paramount to p75 signaling (Lee et al,. 2001) despite the ability of mature neurotrophins such as NGF to bind with p75. Furthermore, proBDNF acts in vivo as a biologically active factor regulating hippocampal structure, and synaptic transmission, and plasticity, which mature BDNF impacts differently (Yang et al., 2014). The ability of sortilin to recognize the prodomains or the 3 proneurotrophins: proNGF, proBDNF and pro NT-3, allows for the formation of a co-receptor complex of p75, sortilin and the proneurotrophin. This demonstrates proneurotrophin induced apoptotic signaling at lower ligand concentrations (Nykjaer et al. 2004; Teng et al. 2005; Jansen et al. 2007; Willnow et al. 2008; Yano et al. 2009). SorCS2 is another receptor and gene found within the nervous system. A member of the sortilin family, this receptor binds with a variety of ligands to mediate neuronal activities. Additionally, deficits caused by lack of SorCS2 receptor can result in problems for the organism, as sortilin, a biologically important neurotrophin receptor, targets the pro-domain of proNGF with high affinity (Nykjaer, et al, 2004). However, sortilin deficiency does not affect developmentally regulated apoptosis of sympathetic neurons, or prevent age-dependent degeneration (Jansen, et al., 2007). This study was conducted in order to determine the consequences of growth contraction and synapse elimination. Previously the impacts of the Val66Met polymorphism of BDNF on prodomain structure were determined to impact the structure and function of the protein produced altering growth cone retraction. Previously, a 28% binding differential of the Val and Met isoforms was seen (Anastasia, 2013). Although using Biocore assay was a potential approach, the biology of the prodomain molecule would have most likely caused the protein to stick to the Biocore instead of binding with both Zn2+ and the receptor SorCS2 when they were present. The Biocore also would have made any binding difficult to see. Therefore, using Co-IP with was selected instead. Research Question(s) and Hypotheses: Q1: How does SorCS2 interact with the prodomain? Q2: How does the met SNP influence prodomain effects? H0 Null Hypothesis: They interact differently H1 Refined Hypothesis: The Met prodomain will have more pronounced effects than the Val prodomain. In the presence of Zinc: Val will stay constant and bind with SorCS2 a small amount of binding product will be formed. Met will increase and bind with SorCS2 a large amount of binding product will be formed H2 Protein Purification Hypothesis: If you knock out SorCS2 receptor the Met prodomain will not have any effect. Binding of Prodomain with SorCS2 A previous study (Anastasia, 2013), showed that Met66 prodomain binds differentially and stronger with SorCS2 than the Val66 prodomain (through quantitative analysis). It is possible that the differences in function and structures of the different isoform-containing prodomains have resulted from this binding difference. As a result of the conclusions of this study, it was decided that the impact of Zn2+ (an ion commonly found in the Figure A post-synaptic cleft) on this interaction should be examined more thoroughly. Testing Prodomain Binding to Avidin Agarose beads Test Trial Using Co-IP Conditions: Prodomain, Prodomain + Zn2+, Prodomain + Zn2+ + NaCl (both pre and post beads samples for each condition) Co-IP was performed using Val66 prodomain samples. Following SDS-Page, the membrane was incubated with proBDNF Gene Copeoia antibody (1:10,000 dilution) followed by HRP. Figure
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